tbuckley/cabot-search huggingface dataset:
Abstract 1738: DNA-launched nanoparticle vaccines induce cytolytic T cell responses for <i>in vivo</i> tumor control
Authors: Kevin Liaw, Ziyang Xu, Neethu Chokkalingam, Daniel Kulp, David Weiner
Journal: Cancer Research (2022)

Abstract Nanotechnology-based approaches have achieved promising results for the development of novel immunotherapeutic cancer vaccines through the decoration of antigens on nanoparticle scaffolds for multivalent display. However, their translation have been limited due to challenges with purification, scalability, and robust induction of cytolytic T cell responses critical to anti-tumor activity. We designed a nanovaccine construct by fusing the HPV E7 immunodominant epitope onto lumazine synthase scaffold. We demonstrate that through electroporation-facilitated DNA delivery encoding the antigen-scaffold construct, this nanovaccine is expressed and self-assembles in vivo into 60-mer nanoparticles. Compared to CpG-adjuvanted peptide and monomeric DNA vaccination, this DNA-launched nanovaccine induced greater CD8+ cellular responses against the E7 epitope and target tumor cells. In both flank and lung models of TC-1 HPV-associated cancers, the nanovaccine achieved significant tumor regression and prolonged survival compared to CpG-adjuvanted peptide. Anti-tumor immunity was retained upon rechallenge &amp;gt;150 days after initial challenge, supporting the induction of long-term immune memory. In addition, we demonstrate that this DNA-launched nanovaccine platform can be used to form hybrid nanoparticles displaying multiple antigens simultaneously. These hybrid nanoparticles exhibit synergistic efficacy, with improved tumor control over administration of separate single-antigen nanovaccines. These promising results, along with facile characterization, scalability, and stability, support that DNA-launched nanovaccines can induce potent anti-tumor cellular immunity and are ideally positioned for further translational development for clinical evaluation. Citation Format: Kevin Liaw, Ziyang Xu, Neethu Chokkalingam, Daniel Kulp, David Weiner. DNA-launched nanoparticle vaccines induce cytolytic T cell responses for in vivo tumor control [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1738.
Abstract SY23-02: Elevated cellular stiffness sensitizes metastatic cells to destruction by mechanosurveillance: The mechanical mode of immune surveillance
Authors: Ekrem Emrah Er
Journal: Cancer Research (2022)

Abstract Tumor evolution is coupled to profound biophysical changes in cancer cells and understanding how these changes impact metastasis can reveal novel therapeutic targets. One prominent biophysical characteristic of cancer cells is their stiffness. At the early steps of the metastatic cascade, transformed cells become physically softer and this allows them to invade into and to navigate through the surrounding extracellular matrix. Conversely, cancer cells that later intravasate into circulation need to maintain a higher degree of biophysical stiffness in order to withstand shear forces that otherwise cause mechanical rupture of cancer cells during hematogenous dissemination. However, the impact of cellular stiffness on the final stage of metastatic colonization in vital secondary organs is not well understood. We recently found that increasing stiffness of disseminated cancer cells sensitizes them to destruction by cytotoxic lymphocytes. Specifically, we found that myocardin related transcription factor (MRTFA/B) activity in cancer cells increases cancer cell stiffness, which then biophysically stimulates apoptotic cytokine production and cytolytic granule secretion in the adjoining CD8+ T- and Natural Killer (NK) cells for improved cytotoxicity. Our data highlighted the in vivo prevalence of the fundamental concepts in lymphocyte mechanobiology, which posit that increasing the stiffness of the surfaces that oppose T- and NK cells increases their cytolytic function through mechano-chemical signal transduction. We termed this mechanical mode of immune surveillance “mechanosurveillance” and showed that the expression of its molecular mediators cooperates with immune checkpoint blockade therapies in melanoma models and is associated with better patient survival in the clinic. In our current work, we utilized a series of novel biophysical approaches to measure the stiffness of metastatic foci in situ and to demonstrate that physically stiffer metastatic foci are eliminated by the immune surveillance. Furthermore, we used bioinformatics analyses of patient data and loss-of-function and gain-of-function experiments to identify therapeutically actionable proteins that increase cancer cell stiffness. Our findings revealed pharmacological manipulations that increase cancer cell stiffness and provided a road map for promoting mechanosurveillance in metastatic niches. Citation Format: Ekrem Emrah Er. Elevated cellular stiffness sensitizes metastatic cells to destruction by mechanosurveillance: The mechanical mode of immune surveillance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY23-02.
Metabolic Symbiosis‐Blocking Nano‐Combination for Tumor Vascular Normalization Treatment
Authors: Hui Xiong, Xiaoyan Liu, Zuohan Xie, Linyuan Zhu, Haipeng Lu, Cheng Wang, Jing Yao
Journal: Advanced Healthcare Materials (2022)

The clinical anti-vascular endothelial growth factor (anti-VEGF) drugs and metronomic chemotherapy (MET) induced tumor vascular normalization treatment (TVNT) are easily antagonized by tumor microenvironment metabolic cross-talk between tumor cells and endothelial cells (ECs). To overcome this dilemma, nanodrug with the ability of ECs targeted glycolysis inhibition and nanodrug with the ability of tumor cell glycolysis inhibition, anti-VEGF, and MET are combined to prepare Nano-combination the pathways related to angiogenesis, tumor cell proliferation, and immunosuppression and breaking the negative sugar-lipid-protein metabolism balance in tumor microenvironment. Thus, stronger and more lasting normalized tumor vascular network and remarkable antitumor efficacy are obtained after treatment, constructing a positive feedback loop between TVNT and anti-tumor therapy. Above all, this study provides a new insight for solving the bottleneck of clinical TVNT.
Abstract 1095: Establishment and characterization of a topotecan resistant lung cancer NCI H460/TPT10 cell line and a tumor xenograft model
Authors: Qiu-Xu Teng, Zi-Ning Lei, Wei Zhang, Ying-Fang Fan, Jing-Quan Wang, Chao-Yun Cai, Dong-Hua Yang, John Wurpel, Zhe-Sheng Chen
Journal: Cancer Research (2022)

Abstract While topotecan (TPT) is a chemotherapeutic drug in treating lung cancer, the development of TPT resistance in tumors reserves as a major obstacle to chemotherapeutic success. Therefore, a better understanding of the mechanisms of TPT resistance is critical. In this study, the first topotecan-resistant human non-small cell lung cancer (NSCLC) cell line, termed NCI-H460/TPT10, was established from the parental NCI-H460 cell line. NCI-H460/TPT10 cells exhibited a 394.7-fold resistance to TPT, and cross-resistance to SN-38, mitoxantrone, and doxorubicin, compared to parental NCI-H460 cells. Overexpression of ABCG2 localized on the cell membrane, but not ABCB1 or ABCC1, was found in NCI-H460/TPT10 cells, indicating that ABCG2 was likely to be involved in TPT-resistance. This was confirmed by the abolishment of drug resistance in NCI-H460/TPT10 cells after ABCG2 knockout. Moreover, the involvement of functional ABCG2 as a drug efflux pump conferring multidrug resistance (MDR) was indicated by low intracellular accumulation of TPT in NCI-H460/TPT10 cells, and the reversal effects by ABCG2 inhibitor Ko143 and cabozantinib. The NCI-H460/TPT10 and its parental cell line were further used to establish in vivo tumor xenograft mouse models, which verified their capability to serve as clinically relevant models for drug screening and the development of targeted strategies to overcome ABCG2-mediated MDR in NSCLC. Citation Format: Qiu-Xu Teng, Zi-Ning Lei, Wei Zhang, Ying-Fang Fan, Jing-Quan Wang, Chao-Yun Cai, Dong-Hua Yang, John Wurpel, Zhe-Sheng Chen. Establishment and characterization of a topotecan resistant lung cancer NCI H460/TPT10 cell line and a tumor xenograft model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1095.
Abstract 5734: The effect of PRAME on retinoid response and cell proliferation in cutaneous and head and neck squamous cell carcinoma
Authors: Brandon Liam Ramchatesingh, Ivan Litvinov
Journal: Cancer Research (2022)

Abstract As cells undergo terminal differentiation, they adopt their tissue-specific functions and permanently exit the cell cycle. Inducing differentiation of premalignant cells and malignant cells are proposed strategies for cancer prevention and treatment, respectively. Retinoids, compounds related to retinol, drive terminal differentiation of numerous cell types. These compounds exhibit efficacy for the prevention of cutaneous squamous cell carcinomas (cSCC) and head and neck squamous cell carcinomas (HNSCCs), and their incorporation into treatment plans for these cancers is supported by laboratory and clinical studies. Preferentially Expressed Antigen in Melanoma (PRAME) is a cancer-testis antigen that represses retinoid signaling, and is associated with adverse outcomes in a plethora of malignancies. Although PRAME is known to be expressed in subsets of cutaneous SCC (cSCC) and head and neck SCC (HNSCC) tumors, its functions, prognostic and therapeutic significance have never been investigated in these cancers. We hypothesize that PRAME expression in SCC cells confers resistance to the anti-neoplastic effects of retinoids and supports cell proliferation. PRAME expression was evaluated in human cSCC tumors, and in cSCC and HNSCC cell lines by immunoblotting and qRT-PCR. PRAME-overexpressing immortalized keratinocyte, cSCC and HNSCC cell lines were generated. shRNA-mediated knockdown of PRAME was performed in a cSCC and a HNSCC cell line. Cells were treated with all-trans retinoic acid (ATRA) for 24, 48 or 72 hours. Expression of differentiation markers was assessed by immunoblotting and qRT-PCR of markers of differentiation. Cell counting assays, immunoblot analysis of cell cycle genes and Ki67 immunofluorescence staining were used to assess proliferation. PRAME expression is detected in subsets of cSCC tumors and in select SCC cell lines. Overexpression of PRAME in HNSCC cells enhanced cell proliferation compared to control cells. Treatment with ATRA did not promote differentiation of PRAME-expressing cells. Furthermore, PRAME overexpression attenuated the anti-proliferative effect of ATRA in HNSCC cells. We conclude that PRAME enhances proliferation of malignant keratinocytes in vitro and may confer resistance to retinoid-induced differentiation and proliferation arrest. Investigations to assess the prognostic and therapeutic significance of PRAME expression in SCCs are warranted. Citation Format: Brandon Liam Ramchatesingh, Ivan Litvinov. The effect of PRAME on retinoid response and cell proliferation in cutaneous and head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5734.
Abstract 1726: Novel, high-throughput multiplexed immunofluorescence staining method for assessing spatial relationships of immuno-oncology biomarkers in whole slide FFPE tissue
Authors: Rachel Schaefer, Linying Liu, Michael McLane, Oscar Perez, Jacob Circelli, Carla Coltharp, Yi Zheng
Journal: Cancer Research (2022)

Abstract As cancer research has progressed, the role of the immune system in tumor development has been discovered to be increasingly more important. There is a need to explore the spatial relationships between tumor and immune cells in tissue to help better predict therapeutic treatment outcomes in patients in the growing field of immuno-oncology. We have developed a new single cell multiplexed immunofluorescence staining method along with our patented multi-spectral imaging (MSI) technology to allow scientists to detect up to six biomarkers simultaneously on one tissue section, which provides an end-to-end, fully automated workflow from staining to image analysis. In this study, we show a methodology that allows primary antibodies to be applied as a single cocktail in one incubation step followed by amplified detections using Opal fluorescent dye technology. Formalin-fixed paraffin-embedded (FFPE) samples were stained on the Leica BOND RX࣪ automated staining system using our new multiplex procedure and compared to 3,3′-Diaminobenzidine (DAB) chromogenic immunohistochemistry assay. Multispectral scans were acquired on the Akoya Vectra Polaris® imaging system with optimized acquisition parameters. Image analysis was performed with a phenotyping algorithm in inForm® analysis software and intensity analysis was performed in R using phenoptr and phenoptrReports. The six multiplexed biomarkers are shown to be comparable in staining patterns to their DAB counterparts. Whole slide image scans were successfully unmixed and treated as individual monoplexes, but combined at will to observe the spatial relationships. This easy-to-use staining method simplifies tissue-based multiplex immunofluorescence by providing primary antibody cocktailing and cyclic deposition of fluorescent Opal dyes while maintaining strong staining intensity and the ability to spectrally unmix different wavelengths from the image for visualization and spatial analysis. This novel method will provide researchers with a flexible and readily available solution for staining patient samples to investigate spatial phenotypic signatures, aiding in the development of targeted immune therapies. Citation Format: Rachel Schaefer, Linying Liu, Michael McLane, Oscar Perez, Jacob Circelli, Carla Coltharp, Yi Zheng. Novel, high-throughput multiplexed immunofluorescence staining method for assessing spatial relationships of immuno-oncology biomarkers in whole slide FFPE tissue [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1726.
Abstract 5040: Genetic predisposition of rectal neuroendocrine tumors
Authors: Subrata Saha, Adina Grunn, Andrea Califano
Journal: Cancer Research (2022)

Abstract Rectal neuroendocrine tumors (RNETs) represent a clinically and molecularly distinct, yet poorly characterized subtype of gastroenteropancreatic neuroendocrine tumors (GEP-NET), with a virtually uncharted genetic landscape. Given their rare nature, compared with their small intestine (SI-NET) or pancreatic (PNET) counterpart, there have been no systematic efforts to elucidate the genetic landscape of RNETs and understand whether these tumors may present a common genetic etiology and predisposition. We have assembled a discover and a validation cohort comprising blood and tumor samples from 31 and 21 metastatic RNET patients, respectively, which was very challenging given the ultra-rare nature of these tumors. Whole-exome profiles were used to identify both rare and common germline variants that may be predictive of metastatic RNET predisposition, which is suspected to have a strong genetic component, given their frequent multifocal presentation. Among nonsynonymous rare germline variants (MAF &amp;lt; 0.05 in the general population), 314 were significantly over-represented in the discovery cohort (FDR ≤ 0.05), based on ethnicity-matched controls from the 1,000 Genome Project. Of these, 144 were also identified in samples from the validation cohort. Of the 40 that were statistically significant in both cohorts, 11 were deemed pathogenic by CADD Phred-scores analysis (≥ 20.0), including 8 in regulatory regions. This includes pathogenic variants harbored by ALKBH8, LRRC71, PSPH, MUC16, SCRT2, YARS, MICAL3, KDM6B, SYCP2L, and TTN. We validated six statistically significant variants in both cohorts by Sanger sequencing. Critically, a classifier trained on the 314 statistically significant variants in the discovery cohort produced perfect classification (area under the receiver operator curve AUROC = 1) in predicting the tumor bearing vs. healthy individuals in the validation cohort and in an equivalent number of ethnicity matched control samples, shuffled 1,000 times. Moreover, a weighted, graph-based biological pathway analysis method identified co-segregation of genes harboring tumor-predictive variants in cancer related pathways, including genome integrity, DNA replication fidelity, extracellular matrix organization, glycosylation, and the inflammasomes, among others. Taken together, these results support a common, uniquely distinctive genetic etiology for RNETs, suggesting a strong germline predisposition. More critically, the accuracy and sensitivity of the predictor suggests that these rare variants may be effectively used as a biomarker to identify individuals at risk of developing RNETs. Citation Format: Subrata Saha, Adina Grunn, Andrea Califano. Genetic predisposition of rectal neuroendocrine tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5040.
(1 → 3)-β-d-Glucan-guided antifungal therapy in adults with sepsis: the CandiSep randomized clinical trial
Authors: Frank Bloos, Jürgen Held, Stefan Kluge, Philipp Simon, Klaus Kogelmann, Geraldine de Heer, Sven-Olaf Kuhn, Dominik Jarczak, Johann Motsch, Gunther Hempel, Norbert Weiler, Andreas Weyland, Matthias Drüner, Matthias Gründling, Patrick Meybohm, Daniel Richter, Ulrich Jaschinski, Onnen Moerer, Ulf Günther, Dirk Schädler, Raphael Weiss, Christian Putensen, Ixchel Castellanos, Oliver Kurzai, Peter Schlattmann, Oliver A. Cornely, Michael Bauer, Daniel Thomas-Rüddel, Ulrich Jaschinski, Christian Putensen, Matthias Drüner, Ixchel Castellanos, Stefanie Schmidt, Andreas Wehrfritz, Diana Kränzlein, Jürgen Held, Kai Zacharowski, Haitham Mutlak, Simone Lindau, Carolin Wiedenbeck, Onnen Mörer, Sven-Olaf Kuhn, Matthias Gründling, Stephan Kluge, Geraldine de Heer, Dominik Jarczak, Johann Motsch, Daniel Richter, Markus A. Weigand, Frank Bloos, Michael Bauer, Daniel Thomas-Rüddel, Peter Schlattmann, Thomas Lehmann, Norbert Weiler, Dirk Schädler, Oliver A. Cornely, Philipp Simon, Gunther Hempel, Raphael Weiss, Alexander Zarbock, Ulf Günther, Georg Rohe, Andreas Weyland, Oliver Kurzai, Grit Walter, Patrick Meybohm, Philipp Helmer
Journal: Intensive Care Medicine (2022)

To investigate whether (1 → 3)-β-d-Glucan (BDG)-guidance shortens time to antifungal therapy and thereby reduces mortality of sepsis patients with high risk of invasive Candida infection (ICI). Multicenter, randomized, controlled trial carried out between September 2016 and September 2019 in 18 intensive care units enrolling adult sepsis patients at high risk for ICI. Patients in the control group received targeted antifungal therapy driven by culture results. In addition to targeted therapy, patients in the BDG group received antifungals if at least one of two consecutive BDG samples taken during the first two study days was ≥ 80 pg/mL. Empirical antifungal therapy was discouraged in both groups. The primary endpoint was 28-day-mortality. 339 patients were enrolled. ICI was diagnosed in 48 patients (14.2%) within the first 96 h after enrollment. In the BDG-group, 48.8% (84/172) patients received antifungals during the first 96 h after enrollment and 6% (10/167) patients in the control group. Death until day 28 occurred in 58 of 172 patients (33.7%) in the BDG group and 51 of 167 patients (30.5%) in the control group (relative risk 1.10; 95% confidence interval, 0.80–1.51; p = 0.53). Median time to antifungal therapy was 1.1 [interquartile range (IQR) 1.0–2.2] days in the BDG group and 4.4 (IQR 2.0–9.1, p < 0.01) days in the control group. Serum BDG guided antifungal treatment did not improve 28-day mortality among sepsis patients with risk factors for but unexpected low rate of IC. This study cannot comment on the potential benefit of BDG-guidance in a more selected at-risk population.
Abstract 60: Functional mapping reveals widespread remodelling and unrecognized pathway dependencies in recurrent glioblastoma
Authors: Chirayu R. Chokshi, Kevin Brown, Chitra Venugopal, Jason Moffat, Sheila K. Singh
Journal: Cancer Research (2022)

Abstract Glioblastoma is a highly fatal brain cancer. The underlying functional drivers of treatment resistance and disease recurrence are unclear. By applying a genome-wide CRISPR-Cas9 library to patient-derived glioblastoma stem cell models, we systematically map genetic dependencies in patient-matched pre-treatment primary and post-treatment recurrent tumor cells. These insights reveal a large-scale remodelling of genetic dependency profiles at disease recurrence, arming recurrent tumor cells with newly-acquired genetic drivers and further loss of tumor suppressors. These analyses support parallel tumor-intrinsic mechanisms of treatment resistance which rely on acquisition of immunosuppressive capacity, including a defective mismatch repair pathway, ablation of PTEN activity, and a novel combination of de novo mutations in SWI/SNF components. We map a multilayered genetic and functional response to drive tumor recurrence, identifying protein tyrosine phosphatase 4A2 (PTP4A2) as a novel driver of self-renewal, proliferation and tumorigenicity at glioblastoma recurrence. Mechanistically, genetic perturbation and a small molecule inhibitor of PTP4A2 results in greater survival and reduced tumor growth in patient-derived models of recurrent glioblastoma. Citation Format: Chirayu R. Chokshi, Kevin Brown, Chitra Venugopal, Jason Moffat, Sheila K. Singh. Functional mapping reveals widespread remodelling and unrecognized pathway dependencies in recurrent glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 60.